Prevention research gave H IV medicine its first ironclad success,
back in the days when few considered the words success and HIV medicine
in even remotely related brainwaves. It happened on February 17, 1994,
when a panel reviewing data from Pediatric AIDS Clinical Trials Group
(PACT(;) study 076 learned that zidovudine monotherapy taken during
pregnancy by previously untreated women slashed the risk of HIV
transmission by two thirds. (1,2) Since then, more muscular prophylactic
regimens have cut mother-to-child transmission risk to about 1%.

Other biomedical HIV prevention successes followed. Postexposure
prophylaxis (PEP), if begun soon after viral contact and taken
faithfully, protects most people exposed to HIV on the job or in the
bed? Three randomized trials found that circumcision cuts the risk of
sexually acquired HIV in heterosexual men. (4-6) And getting your sex
mate to don a condom usually contains the virus, as long as the condom
doesn't break.

But there's also a dark side to HIV prevention research, one
that has yielded hardly a pinprick of light in more than two decades of
labor. The bleak record of attempts to find an HIV vaccine has already
provided enough fodder for a book-long catalog of woe, (7) and that book
came out years before the latest headline-spangled failure. Three
placebo-controlled trials of acyclovir to control herpes simplex virus
type 2 (HSV-2) as a way to lower HIV risk ended in failure, (8-10) as
did six trials aimed at identifying a vaginal microbicide to block HIV.
(11-16) The most recent microbicide trial vouchsafed a glimmer of hope
with an agent called PRO 2000. (17)

What explains this incessant string of failures in three critical
prevention areas? Is it just that finding a vaccine, a microbicide, or
an HSV-2 blocker that limits HIV risk is hard? Or, as more than one
scientist suggests, is it that prevention planners have bull-headedly
pushed through studies of candidates bound to fail? These explanations
are not mutually exclusive. Indeed, evidence backing both possibilities
is rife in the annals of prevention research.

No one doubts that HIV prevention remains an exigent priority. The
latest global head count tallied 2.7 million new infections in 2007, and
1 million people starting antiretroviral therapy. "So do the
math," suggests Ward Gates of Family Health International in an
interview with RITA! "We're losing the battle against HIV
unless we have more tools." Improving prevention is no less urgent
in the United States, where the Centers for Disease Control (CDC)
revamped its long-standing estimate that 40,000 people pick up HIV every
year, jacking that annual reckoning to 56,000. (18)

This issue of RITA! ponders that evidence with assists from 12
experts in prevention research, three of whom spelled out their thinking
in extended telephone interviews (see pp. 26.29, 34).

Rapidly cycling prospects for an HIV vaccine

More ink has been spilled than plasma in trying to figure why
making even a modestly effective HIV vaccine has proved impossible for
over two decades. The latest inky inundation followed failure of
Merck's gag/pol/nef-adenovirus vector candidate in the STEP trial
(19,20) and subsequent speedy shutdowns of two related studies, Phambili
(testing the same vaccine in South Africa (21)) and PAVE 100 (testing an
HIV DNA vaccine with the same adenovirus vector in the United States
(22)).

This retrenchment is only the latest chapter in a largely
inglorious history of HIV vaccine development. The endeavor began with
bright hopes in 1984, when discovery of HIV-1 prompted US health chief
Margaret Heckler to predict an HIV vaccine would be ready for testing in
2 years. Heckler, a long-time Republican pol considered for a NASA job
just before becoming Ronald Reagan's Secretary of Health, learned
to her regret that retrovirology is tougher than rocket science. Knowing
little then about HIV's relentless mutability, few scientists
stepped forward to challenge this brassy assertion. In fact,
Heckler's office based the prediction on input from Robert Gallo,
according to Science reporter Jon Cohen. (7) And many HIV vaccine
researchers went on to suggest routinely that the world would have an
HIV vaccine "in 10 years," though they offered that augury
repeatedly as calendar pages flew by.

With the turn of the millennium come and gone and no vaccine in
sight, some credible experts began counseling that an HIV vaccine may
never be made. Anthony Fauci, head of the National Institute of Allergy
and Infectious Diseases (NIAID) and the country's most visible
vaccine spokesman, counseled in 2004 that "all of us are working
under the assumption that we will [develop a vaccine], but there's
certainly the possibility that we're not going to be able to
develop a truly effective preventive vaccine." (23)

And at the 2008 Conference on Retroviruses, after the Merck
failure, Harvard's Ronald Desrosiers warned, "there is no
rational basis for believing that any of the products in the pipeline
have any chance of effectiveness. Dollars that could have been used for
discovery research have been used to manufacture and test products that
have little hope." (24)

What went wrong? Does HIV vaccine research resemble a staccato
volley of "shots in the dark," as Jon Cohen suggested in
titling his coruscating account of vaccine science in 2001. (7) Angus
Dalgleish, who identified CD4 as HIV's primary cellular receptor
and studies HIV and cancer immunology at St. George's University in
London, thinks vaccine planning pros still shoot blindly, though he
mostly eschews dainty metaphor:

"The people at the top of the research and funding agendas
have an extreme version of tunnel vision," Dalgleish told RITA! by
e-mail. They "ignore the strong signals that HIV is different from
other viruses which can be successfully prevented by vaccines. Even most
of the immunologists involved are blind men feeling an elephant."

The University of Pennsylvania's David Weiner, a champion of
DNA vaccines, also believes ideology can derail research planning,
though he suggests there's a good reason: "Scientists have
strong opinions and these are important as they are asked to invent a
safer future," he told RITA! "They live on the edge of the
scientifically possible and they need the conviction to jump of f the
edge." But, Weiner insists, scientists must remember "balance
is key and not ideology."

Now, fewer than 2 years after STEP, Phambili, and PAVE
investigators closed shop, some prevention mavens sound propitious once
more. Anthony Fauci told RITA! "we are certainly not giving
up" on devising a vaccine that confers sterilizing immunity.
"I have cautious optimism that we will be able to do it." (See
the interview with Dr. Fauci on p. 26.)

The University of North Carolina's Myron Cohen thinks
"the vaccine field is making progress" because "the basic
science is moving very fast right now." (See the interview with Dr.
Cohen in this issue.)

Even Ronald Desrosiers, the last person one would call an HIV
vaccine Pangloss, sees reason for hope, he told RITA! "I believe
that the approach described by Phil Johnson at this year's CROI
meeting (25) has the potential of conferring sterilizing immunity
against the majority of strains circulating around the globe." (See
below for more on Johnson's strategy.)

Dare one espouse a rosy outlook so soon after the resounding rout
of a vaccine called "promising" so routinely that people
assumed it was part of the vaccine's name? A look at how vaccine
research got where it is today suggests no need to abandon all hope.

What should an HIV vaccine do?

As surprising as it sounds, that remains a contentious question.
Some say the only sensible HIV vaccine must stimulate antibodies that
recognize HIV and neutralize it before infection takes hold. Others say
a vaccine that stirs up HIV-killing T cells, like the Merck vaccine,
would be a big step forward. A third contingent insists a successful
vaccine must do both. And a fourth party proposes skinning the virus
some other way entirely.

HIV vaccine efficacy trials began (notoriously) with two trials of
AIDSVAX, which tried to pique neutralizing antibodies by subjecting
high-risk populations to a recombinant mimic of HIV's gp120
envelope protein (Table 1 on page 8), (26,27) Almost everyone--except,
apparently, the investigators and the developer--believed from the start
that AIDSVAX would flop because HIV's envelope mutates so avidly
and because neither monoclonal antibodies to gp 120 (28) nor envelope
subunit vaccines (29) neutralized viral isolates from people--they
worked only on lab strains.

And flop it did, inspiring near unanimity on two points: First,
mounting vaccine efficacy trials on a scaffold of shaky science is a
dreadful waste of human and financial capital. And second, tricking the
body into making antibodies that handcuff HIV is every bit as hard as
predicted. Years after the AIDSVAX flameout, how to elicit neutralizing
antibodies still vexes the most thoughtful scientists. Indeed, research
has yielded few clues on which antibodies to summon, although several
investigators doggedly pursue antibody vaccine leads.

Difficulties with the antibody approach did much to stoke interest
in a vaccine that sparks cell-mediated immunity. Cell-mediated immunity
won't protect a person from HIV, because HIV-specific T cells go
after already-infected cells. But, in theory, cell-based immunity could
keep HIV replication under wraps long enough to delay antiretroviral
therapy, and well enough to keep infected people from spreading HIV to
sex mates.

Merck's MRKAd5 vaccine aimed to harness HIV by stimulating
HIV-fighting cells in a double-blind, placebo-controlled trial at 34
sites in North America, the Caribbean, South America, and Australia.
(19,20) An interim analysis found that, among people with a prestudy
adenovirus 5 (Ad5) antibody titer below 201, 24 of 741 people (3%)
getting the vaccine and 21 of 762 (3%) getting dummy shots picked up HIV
infection. (19) Looking at all study participants regardless of prestudy
Ad5 antibody levels, the researchers found a 2-fold higher risk of HIV
infection in Ad5-positive men who got the vaccine than in the placebo
group (hazard ratio 2.3, 95% confidence interval 1.2 to 4.3). Even
though the vaccine induced HIV-specific CD8 cells, (20) it did not lower
the HIV load set point significantly more than placebo. (19)

Although the media reported the Merck failure in doomsday
vernacular and scientists thrashed vigorously for explanations, more
than a few vaccine savants saw little reason for surprise. Indeed, some
had predicted failure before the bad news came. NIAID's Anthony
Fauci and Margaret Johnston noted skepticism that the Merck vaccine or a
prime-boost vaccine "will be effective in the prevention of HIV
infection" in the May 17, 2007 New England Journal of Medicine.
(30)

As long ago as 2001, Dutch virologist Jaap Goudsmit baldly stated
that vaccines aimed at stirring cell-mediated immunity "will never
do anything else than postpone AIDS ... [and] they will not block or
hamper spread [of HIV] substantially." (31)

After the STEP trial bust, Fauci shut down an already-truncated
version of the PAVE study, designed to test a similar vaccine.
STEP's collapse, Fauci said in a Scientific American interview, led
some to say, "Well maybe we can look at the immunological response
and get some information from a subset of people in the trial who seem
to have responded well." (32) But "that's a fallacious
approach," he maintained. "If the vaccine doesn't work,
doing immunological correlates, in my mind, and the minds of many many
of my colleagues, is not worth doing."

Is there any reason to continue working on T-cell vaccines for HIV?
"No," Angus Dalgleish told RITA! "Even my dog sees this
one."

But David Weiner counters that "the same question could be
raised for antibody approaches following the VaxGen studies (26,27)
where antibodies had no impact." The University of Pennsylvania
vaccine expert explains that the Merck vaccine "induced a low level
of interferon-gamma ELISPOT response against perhaps only three [viral]
epitopes at a very low magnitude, well below those levels in infected
persons that control infection." On top of that, the vaccine
stirred such responses in only 60% to 70% of vaccinated people, and
higher HIV incidence in people with high Ad5 levels confused
interpretation of results.

"But," Weiner adds, "as soon as a true cytotoxic T
lymphocyte [CTL] vaccine is developed that in people drives CTLs at a
greater rate, and stronger magnitude, and more breadth, I would be in
favor of a small focused study."

Stanley Plotkin, who devised the rubella vaccine and worked on
several other viral vaccines at Philadelphia's Wistar Institute,
agrees with Weiner. "It is still clear that some forms of cellular
immunity control viral load," he told RITA! In a post-STEP review
article, Plotkin pointed to "numerous leads with regard to
improving cellular immune responses to an HIV vaccine." (33)
Failure of the Merck candidate, he added, "says only that the
responses induced were inadequate to simulate those induced during
natural infection that appear to control HIV temporarily."

Jorge Flores, deputy director of a vaccine research program at
NIAID, confirms that "the field has been polarized pro/against
continuing development of T-cell vaccines." But "such
polarizations are not uncommon in science," he adds, "and at
the end may be useful." Arguing that a combined antibody/T-cell
vaccine would be "ideal," Flores cautions that "the
T-cell concept should not be dropped prematurely."

But whether anyone will sponsor another T-cell vaccine trial, when
no one expects that kind of vaccine to prevent infection, remains open
to question. More data on T-cell and antibody-stimulating approaches
will come from a nearly finished phase 3 Thai trial of a vaccine
intended to excite T-cell responses with HIV-1 subtype E gag, pro, and
env, and to elicit an antibody response with subtypes B and E gp 120.
This prime-boost vaccine survived a preliminary efficacy review, but
Fauci and Johnston observe that this candidate "does not induce
broadly neutralizing antibodies" and they note scientific doubt
about its chances. (30)

Looking for ways forward, looking for funds

With researchers at sixes and sevens over the rationale for
stimulating cell-mediated immunity, work to find a stout
antibody-stimulating vaccine is moving back to the front burner. In an
interview in this issue of RITA!, NIAID chief Fauci confirms the
renascent search for an antibody vaccine, pointing to research by NIAID
investigator Peter Kwong (34) and Scripps Research Institute scientist
Dennis Burton. (35)

The "reverse immunization" approach taken by Philip
Johnson at Children's Hospital in Pennsylvania--touted by vaccine
veteran Ronald Desrosiers--starts by pinpointing broadly neutralizing
antibodies then synthetically fashions genes that produce those
antibodies and ferries them to cells on an adenovirus vector. (25) This
strategy produced high levels of simian immunodeficiency virus
(SIV)-specific antibodies in monkeys after a single injection, and those
levels persisted for up to a year. The antibodies protected six of nine
moneys from intravenous SIV challenge 1 month after injection. All six
unvaccinated monkeys became infected after challenge. Johnson plans to
pursue approval for trials in humans.

Stimulating antibody responses, stimulating T cells, and doing both
are not the only conceivable vaccine tactics. In his e-mail to RITA!
Dalgleish proposed that "the way forward is a therapeutic vaccine
based on the activating ligands which, because they are nonneutralising,
have been ignored by the field." He suggests that a vaccine
preventing ligand activation may prevent viral dispersal and "could
be an ideal preventative as well."

Despite the back-to-basics bent stressed after STEP, several
vaccine deans, including Fauci, caution against abandoning clinical
research entirely until a strong candidate emerges. University of
Pennsylvania scientist David Weiner believes "a focus on basic
research without clinical research is not the best course." Animal
models are useful, Weiner maintains, but studies in humans, "even
vaccine efficacy trials, are critical to moving forward." Though
disappointing, the AIDSVAX and STEP trials advanced the field by
"forcing us to face our failures and move forward."

Stanley Plotkin told RITA! the need for more basic research is
clear. "However," he added, "if a candidate looked really
good in a robust simian model, I would consider a phase 2b trial."

Both basic and clinical research can be expensive. Monkeys for SIV
studies carry a high price tag, and the bigger the human trial, the
bigger the budget. Right now the National Institutes of Health spend
about $600 million yearly on HIV vaccine research. (26) But is that
enough, and is it going to the right labs?

NIAID's Flores thinks NIH and Gates Foundation dollars are
flowing in the right direction. After STEP, both "promptly switched
the discovery/development balance to attend to the new information in
the field and support more basic innovative research," he told
RITA! Still, Flores sees a need for "additional funding to engage
folks outside the field with new ideas and perspectives to
cross-fertilize with HIV vaccine researchers."

But David Weiner argues that "the entire NIH vaccine budget is
a few fully equipped fighter planes, a few pork programs." He
suggests that funders "consider the payoff" of investing in
basic and clinical research: "Through this research we live longer,
healthier lives and generate a tremendous number of jobs and help to
support our economy and help America compete in the global
economy."

Suppressing HSV-2 to prevent HIV acquisition or transmission made
as much sense as circumcising men to lower HIV risk. Volumes of
epidemiologic data backed each strategy as a seemingly surefire bet to
protect people from HIV. When researchers tested circumcision as a way
to limit men's risk of picking up HIV, it worked consistently in
three randomized trials of immediate versus deferred circumcision. (4-6)
When researchers tested HSV-2-suppressive acyclovir therapy as a way to
slow HIV in three placebo-controlled trials, it failed every time (Table
2 on page 1 2). (8-10)

Ate these contrasting trial results merely a stern object lesson on
the limits of cohort data? Or do they also hold lessons on the value of
treating any sexually transmitted infection (STI) as a tool to trim HIV
incidence? Some experts are suggesting the second, broader implication
may apply as well as the first.

1. HSV, especially chronic HSV infection, "may play too small
a role in HIV acquisition to be detectable" in trials.

2. HSV-2 "suppression with acyclovir may be incomplete,
leaving residual microulceration/ inflammation and thus be insufficient
to prevent infection."

3. "The associations between HSV and HIV infection reported in
observational studies may not reflect causality, but rather may be due
to confounding by high-risk behaviors which put individuals at risk of
both HSV and HIV." In other words, herpes simplex infection may not
lead to HIV acquisition, but rather high-risk behaviors lead to both
infections, "and since HSV is more infectious [than HIV], people
acquire it before they acquire HIV."

In an editorial with coworker Maria Wawer, Gray noted that African
studies on what causes genital ulcers fail to pinpoint specific
pathogens in many ulcers, "so ulceration unrelated to HSV-2 could
have diluted the expected effect" of acyclovir. (39)

If acyclovir is too wimpy to affect HIV incidence, would
valacyclovir do the job? Two randomized trials found that people taking
valacyclovir instead of placebo shed less HIV in genital secretions,
(40,41) a result implying that valacyclovir could dampen HIV
transmission. But acyclovir also reduced HIV genital HIV shedding in
some studies, (42,43) and the Partners in Prevention trial found that
giving acyclovir to people already infected with HIV did nothing to
protect their sex mates. (10) Whether valacyclovir would do better is
anybody's guess.

Even if acyclovir therapy had helped block HIV infection, no one
ever proposed rolling out a massive acyclovir program to dampen the HIV
epidemic. "It seems unlikely that HSV-2 suppression interventions
could be provided to all HSV2-infected individuals in low-resource
settings," University of Washington investigator Scott McClelland
explained in an e-mail to RITA! "Nonetheless," he added,
"these types of interventions, if proven to be effective, could be
useful if targeted towards those most at risk for sexual acquisition or
transmission of HIV. For example, interventions targeting female sex
workers and men who have sex with men could benefit these groups
directly, and might also have population-level benefits." But now
it seems even targeted intervention would prove futile.

Prevention experts hasten to stress that dim results of the
acyclovir trials do not mean HIV physicians should forget about treating
HSV-2 and other STIs in people with or at risk of HIV infection. Cohen
and coauthors (37) observe that, besides the inherent clinical value of
controlling non-HIV STIs, having these people in care can yield HIV
benefits because they are more likely to have unrecognized HIV (44) or
to become infected with HIV (45) than people without STIs.

But some prevention bigwigs are beginning to counsel that STI
control should be dropped as an HIV prevention tactic. Dire data backing
their argument go beyond the three hope-dashing acyclovir trials. In
their editorial,: (39) Gray and Wawer note that five of six African
trials testing bacterial infection therapy to slow HIV also found no
impact on HIV incidence. (46-50) And the sixth trial involved a
population with an HIV rate atypically low for Africa. (51) Adding the
three acyclovir trials means seven of eight trials testing this tactic
flopped.

Despite this record of failure, Gray and Wawer observe that many
agencies and HIV programs continue to advise STI control as a way to
bridle HIV. But the trial record strongly argues that pursuing this
discredited strategy only robs funds from proved prevention measures.
They quote Thomas Henry Huxley's apothegm that "the great
tragedy of Science" is "the slaying of a beautiful hypothesis
by an ugly fact." Ugly facts from the STI trials, Gray and Wawer
propose, should inspire some fast adjustments in HIV prevention policy.

Microbicide hopes after first-generation failures

Microbicide trials have an even bleaker record than acyclovir
trials. Whereas three acyclovir trials found no hint that treating HSV-2
cornered HIV, six microbicide trials came up empty. (11-16) Yet
microbicide researchers remain brimful of hope that a vaginal gel can
protect women from HIV. Three factors explain the starkly differing
prospects for these two prevention schemes:

1. Microbicides that failed so far come in two classes that--at
least in retrospect--have long odds against success.

2. Newer microbicides rely on antiretrovirals, which certainly
stymie HIV when taken orally.

3. The most recent trial of a first-generation microbicide offered
some hints of success, (17) and a much larger trial of that agent is
nearly wrapped up.

As Zeda Rosenberg of the International Partnership for Microbicides
explains in an interview in this issue of RITA!, the first microbicides
tested in efficacy trials, nonoxyno (1-9) and SAVVY, (11-13) work on
surface membranes. As a result, they can harm cells as readily as HIV,
and in trials these so-called surfactants apparently ravaged cells more
than they wracked HIV. Unlike surfactants, the polyanions--Carraguard,
(14) cellulose sulfate, (15) and PRO 2000 (17)--have intrinsically limp
antiretroviral activity.

So why did these agents ever make it into big efficacy trials?
Rosenberg observes that microbicide studies started in the early 1990s,
before anyone understood how profoundly the right antiretroviral mix can
stifle HIV. Other experts are more critical. The Gladstone
Institute's Robert Grant and a starry cast of coauthors blame
"poor coordination among interested parties and the choice of
nonvalidated scientific targets for phase III studies." (52)

In a trial comparing the polyanion PRO 2000, the spermicide
BufferGel, and placebo in 3099 African and US women, 36 women using 0.5%
PRO 2000, 54 using BufferGel, and 53 using placebo picked up HIV. (17)
In the primary intention-to-treat analysis, those results meant PRO 2000
had a 30% protective effect compared with placebo, but the difference
between PRO 2000 and placebo stopped short of statistical significance
(P = 0.10). A 33% protective effect would have been statistically
significant.

After a dispiriting string of microbicide failures, that
hair's-breadth distance from unmitigated success looked pretty good
to some prevention experts. In a phone interview, Ward Cates of Family
Health International argued that "there is nothing magic about a
0.05 traditional level" for statistical significance. The 0.05
benchmark signifies a 1 in 20 probability that a result occurred by
chance alone. The trial found that PRO 2000 had "about a 1 in 17
probability of occurring by chance alone--close enough to provide
encouragement."

In an interview in this issue of RITA!, Cohen claims to be
"very encouraged because PRO 2000 is incredibly better than
nothing. As a vehicle, it's incredibly better than nothing."
Notably, PRO 2000 researchers counted only 33 serious side effects of
complications in 769 women using that microbicide--a rate of 4%. (17)

Whether Cates and Cohen can sustain their cheer will come clear
later this year when results of MDP301, a trial of 0.5% PRO 2000 in more
than 9000 people, are divulged. (53) Until then, microbicide advocates
must make do with subgroup analyses of the completed trial. (17) Among
769 women randomized to PRO 2000, 81% reported better than 85% adherence
to gel use, 72% reported faithful condom use by partners, and 68%
reported better than 85% gel use when partners shunned condoms.
Comparing women who used gel more than 85% of the time with women who
used gel less, the investigators charted a 44% lower HIV rate with PRO
2000 than with placebo. Looking only at women who used gel consistently
with partners who did not wear condoms, PRO 2000 reduced HIV incidence
78% compared with placebo.

Those results suggest that women who use PRO 2000 regularly,
especially when their partners shirk condoms, may sidestep HIV 40% to
80% more of ten than women not using PRO 2000. But as Rosenberg observes
in her RITA! interview, interpreting subgroup analyses gets dodgy
because such analyses lose the objective power of randomization.

Cohen suggests one reason the PRO 2000 findings have not whipped up
wider zeal is the high hope for trials using antiretroviral-containing
microbicides. CAPRISA 004 enrolled 980 South African women with a high
HIV risk and randomized them to use 1% tenofovir gel or placebo. (54)
Results should be ready in 2010. A vaginal microbicide combining
tenofovir and emtricitabine protected 6 of 6 monkeys challenged
vaginally with a simian-HIV mix (SHIV). (55)

Clinical trials of the nonnucleoside dapivirine and the
nonnucleoside UC-781 are under way. As Rosenberg notes, microbicide
researchers are working with antiretroviral makers to plan microbicide
studies of agents in other classes. The microbicide story may still be
in its early chapters.

Preparing for success with PrEP

Antiretrovirals used in vaginal or rectal gels to prevent HIV are
called microbicides; antiretrovirals taken by mouth to prevent infection
are called pre-exposure prophylaxis, or PrEP. McGill University
researcher Mark Wainberg and London clinician Mike Youle were among the
first to espouse antiretroviral-based PrEP, back in 2003. (56,57)
Specifically suggesting PrEP studies of tenofovir because of its low
toxicity and success in postexposure prophylaxis (PEP), Wainberg and
Youle cautioned that developing antiretroviral PrEP "will not be
simple and will take time." (56)

They were right about the complexity, and they were right about the
time. Many prevention pundits also believe they were right about the
potential for success. In an interview in this issue of RITA!, Myron
Cohen affirms a strong belief that antiretroviral PrEP trials "are
going to demonstrate prevention of acquisition, especially heterosexual
penile-vaginal acquisition." And Wainberg's ardor has not
dimmed, he told RITA!, intrepidly predicting that
tenofovir/emtricitabine PrEP trials "will succeed in a major
way."

Tenofovir plus emtricitabine coformulated as Truvada has fomented
particular PrEP fervor, partly because the drugs have a relatively clean
safety record when used daily, partly because they have long
intracellular half-lives, partly because two drugs erect a higher
barrier to resistance than one, and partly because these drugs prevented
rectal SHIV transmission in 4 of 6 monkeys receiving human-equivalent
daily doses and challenged weekly with SHIV for 14 weeks. (58) The two
animals that became infected picked up SHIV on the ninth and twelfth
exposures.

Numerous phase 2 and 3 placebo-controlled trials of PrEP with
tenofovir or tenofovir/emtricitabine are under way in gay men,
heterosexual men and women, discordant heterosexual couples, and
injecting drug users in North and South America, Africa, and Asia. (37)
Mounting these trials wasn't easy. Two early tenofovir PrEP trials
ended before they began, largely at the instigation of AIDS activists
who convinced leaders in Cambodia and Cameroon that the studies were
unethical. (59,60) The protesters claimed the trials lacked adequate
prevention counseling, pre- and post-test HIV counseling, and medical
services and insurance for people who became infected in the studies.
(59)

The principal clinical concern with antiretroviral PrEP is
resistance. If a person taking single- or double-drug PrEP does becomes
infected without realizing it--or unknowingly has HIV before starting
PrEP--the virus will have a splendid chance to replicate in the face of
flimsy treatment, and resistant virus will probably evolve. When that
person's HIV infection is diagnosed, regimens containing drugs to
which the virus has become resistant probably won't work. And if
that person passes HIV to a sex partner before getting suppressive
therapy, the partner will probably pick up the resistant virus.

Resistance risks seem lower with topical microbicides than with
oral PrEP drugs, because microbicides put overwhelming concentrations of
drug at HIV's port of entry--the vagina or the rectum--while
yielding minimal systemic drug levels. In theory, high local drug levels
will keep HIV out, and no virus means no resistant virus. In a US study,
resistant virus did not evolve during 14 days of tenofovir gel use by 24
HIV-infected women. (61) of course, gel adherence will differ in a
14-day controlled trial and in real-world use of vaginal or anal gels,
and imperfect adherence will up the odds of resistance.

Resistance certainly poses a bigger threat with oral PrEP drugs
than with topically applied antiretroviral gels. In the monkey study of
tenofovir/emtricitabine PrEP, the investigators continued giving the
drugs to animals that became infected. (58) The M184I mutation emerged
in one of two animals that became infected while taking oral tenofovir/
emtricitabine. M184I confers resistance to emtricitabine and lamivudine.
The tenofovir-associated K65R mutation did not emerge.

If a person is unknowingly infected before starting tenofovir-based
PrEP or becomes infected despite PrEP, observes Mark Wainberg,
circulating HIV may select resistant virus. "I believe that this
highlights the need to carefully monitor for resistance" in people
taking PrEP, Wainberg told RITA! But the resistance threat is
"certainly not a reason to abandon PrEP." No one advocates
banning antiretroviral therapy because resistant HIV may evolve in
treated people.

PEP after sex or drug use: no waste with baste

Postexposure prophylaxis (PEP) with antiretrovirals has become a
standard of care after health workers get poked with a needle that may
bear HIV or otherwise have a bloody brush with the retrovirus? The
Centers for Disease Control (CDC) also recommends PEP after
"nonoccupational" sexual exposure or needle sharing. For both
occupational and nonoccupational encounters, the CDC calls for PEP only
when "exposure to an HIV-infected source is known or thought to be
highly likely." (3) After contacting blood or other fluids from a
person with uncertain HIV status, the CDC says PEP decisions should be
made "on a case-by-case basis, considering the information
available about the type of exposure, known risk characteristics of the
source, and prevalence in the setting concerned."

When someone needs PEP, it should start as soon as possible,
without waiting for HIV test results, the CDC advises. (3) The agency
does not say which antiretrovirals to use for PEP, suggesting only that
"regimens should aim for simplicity and tolerability," that
pregnant women should not take efavirenz, that no one should take
nevirapine, and that inexperienced physicians should tapan
antiretroviral expert. PEP should continue for 4 weeks, and the PEP
recipient should get tested for HIV within 72 hours if rapid HIV testing
is not available.

Exactly how well PEP works after sex or needle sharing can never be
established because a randomized trial is virtually impossible:
Infection rates in both treated and untreated people would be so low
that only a massive trial could distinguish any difference between PEP
and no PEP. (37) And then there are ethical questions.

There's little doubt, though, that nonoccupational PEP
candidates are legion across the world, according to results of studies
in the United States, (62) Brazil, (63) and Kenya. (64) Researchers in
New York state asked directors of 207 hospital emergency departments to
answer a survey about nonoccupational PEP after sexual assault or
consensual sex. The 188 directors who responded (91%) reported 3439
sexual assaults that may have exposed people to HIV and 6858 consensual
sexual exposures in a single year, 2005. (62) And that leaves out the
likely thousands exposed to HIV by needle or syringe sharing. Notably,
PEP began for only 65% of sexual assault cases and after 43% of
consensual liaisons, even though most hospitals had protocols
recommending PEP.

In Rio de Janeiro, researchers gave 200 HIV-negative gay mena 4-day
supply of zidovudine/ lamivudine and told them to start the drugs if
they had sex with an HIV-infected person. (63) After 2 years of
follow-up, 68 men (34%) started PEP 109 times, and 10 more men should
have because they became infected after deciding not to start PEP. Kenya
launched a national PEP policy in 2001. (64) Between November 2001 and
December 2006, 355 people in western Kenya sought PEP after potential
nonoccupational exposure to HIV, including 285 women and girls (80%) and
90 children (25%).

The few published studies on nonoccupational PEP efficacy show that
it works well, as long as people start fast. A 2005 report from San
Francisco General Hospital involved 877 people beginning a 28-day PEP
course after exposure to HIV in the preceding 72 hours. (65) Among 702
people evaluated 12 weeks after potential exposure, 7 (1%) had HIV
infection. Four of those 7 had another sexual adventure with an
HIV-infected person while on PER The remaining 3 also had sex again, but
they weren't sure of their partner's HIV status. The people
who became infected despite PEP began treatment a median of 45.5 hours
after exposure, while those who remained uninfected started a median of
32.5 hours after exposure. Although that difference falls short of
statistical significance (P = 0.11), it supports advice to start PEP as
soon as possible.

An earlier 401-person study of nonoccupational PEP at San Francisco
General Hospital recorded no HIV diagnoses 6 months after suspected
exposure to the virus. (66) The Brazilian study found only 1 HIV
seroconversion after 109 PEP courses (0.9%). (63) Among 87 PEP patients
with follow-up HIV antibody tests in Kenya, none had HIV infection. (64)
A study of 112 gay men taking two-drug PEP after 116 potential exposures
saw no seroconversions. (67)

The best PEP regimen will probably never be established and will
probably change as antiretrovirals get stronger and safer. Although a
standard three-drug regimen may seem the best bet to keep HIV at bay,
three-drug combinations typically cause more side effects than
double-drug pairs, and side effects dissuade people from completing
their PEP course. So why use three drugs if two will prevent infection?
Comparing tenofovir/emtricitabine or tenofovir/lamivudine with
zidovudine/lamivudine, clinicians at the largest HIV clinic in New
England caring for gay men found that none of 112 people taking
tenofovir-based PEP after 116 exposures stopped of modified their
regimen because of side effects. (67) PEP completion rates were 87.5%
with tenofovir/lamivudine, 72.7% with tenofovir/ emtricitabine, 42.1%
with zidovudine/lamivudine, and 38.8% with zidovudine/lamivudine plus a
third drug.

Even prevention cooperation question breeds controversy

Would the world profit from more cooperation in prevention science?
You'd think this vanilla question would inspire rhapsodic encomiums
to far-flung scientists working shoulder-to-shoulder to halt
transmission of HIV. But you'd be wrong.

As Rosenberg observes in her RITA! interview, health workers will
probably have to cobble together several prevention strategies to keep
HIV at bay--unless a highly effective HIV vaccine emerges. But does the
likely need for manifold prevention tactics mean researchers must always
work together to perfect those tactics? The very notion makes some
scientists' skin crawl.

Johns Hopkins investigator Ronald Gray, who works on several HIV
prevention fronts, doesn't think cooperative research will solve
anything, but will further expand administrative burdens and mix
conflicting agendas. "The current networks for prevention are
already bogged down and underperforming," Gray explained in an
e-mail to RITA! "What science needs is bold vision, careful thought
and individual initiatives, not more committees and conference calls
which waste time and lead to group-think lowest common
denominators." Gray adds that these are precisely the reasons why
the Hopkins team works independently and left a number of NIH networks.

Other prevention mavens only hinted at their disdain for the
committee approach, answering RITA!'s question about cooperation
with an apparently sardonic "I thought that all arms of prevention
science got along well."

(22.) National Institute of Allergy and Infectious Diseases.
Statement: NIAID will not move forward with the PAVE 100 HIV vaccine
trial. July 17, 2008.
(http://www3.niaid,nih.gov/news/newsreleases/2008/pave100.htm).